The metastasis of malignant neoplasms is a significant clinical problem. The death of many patients with cancer is directly or indirectly due to metastases, rather than to the primary neoplasm, which may sometimes even be occult. The current understanding of the pathogenesis of metastatic disease process has evolved from extensive studies, most of which utilized transplantable rodent tumors. Tumors cell heterogeneity has been shown to be an inherent characteristic of many malignant neoplasms and clinically significant metastases occur when specially endowed sub-populations of neoplastic cells successfully complete a complex cascade of events. Although the emergence of "revertants" (sub-populations of neoplastic cells that have lost the capacity to metastasize) has been observed, a thorough examination of the process by which this occurs has not been done. In addition, the study of the processes of metastases of human neoplasms has not been possible until recently. The long term objectives of this project are to study some of the complex biologic processes associated with the metastasis of human neoplasms. To this end an unique model system will be used - that of a human lung carcinoma cell line that spontaneously metastasizes in athymic mice. The specific aims will include 1) selection for "revertants" using endothelial cell monolayers, soft agar cloning and monoclonal antibodies; 2) characterization of the derived revertants and of the metastatic variants using direct biochemical methods as well as monoclonal antibodies. A systematic analysis of the occurrence of reversion to a less malignant phenotype has hitherto been unexplored. The proposed study has been designed to analyse the mechanisms of this reversion in order to eventually elucidate the mechanisms of the malignant disease process. When such mechanisms are understood, therapeutic modalities may then be designed that will encourage this process of reversion of neoplasm thus aborting the inoxerable progression to metastases.